Overcoming CD226-related immune evasion in acute myeloid leukemia with CD38 CAR-engineered NK cells

Luciana Melo Garcia; Achintyan Gangadharan; Pinaki Banerjee; Ye Li; Andy G X Zeng; Hind Rafei; Paul Lin; Bijender Kumar; Sunil Acharya; May Daher; Luis Muniz-Feliciano; Gary M Deyter; Gabriel Dominguez; Jeong Min Park; Francia Reyes Silva; Ana Karen Nunez Cortes; Rafet Basar; Nadima Uprety; Mayra Shanley; Mecit Kaplan; Enli Liu; Elizabeth J Shpall; Katayoun Rezvani

doi:10.1016/j.celrep.2024.115122

Overcoming CD226-related immune evasion in acute myeloid leukemia with CD38 CAR-engineered NK cells

Cell Rep. 2025 Jan 3;44(1):115122. doi: 10.1016/j.celrep.2024.115122. Online ahead of print.

Authors

Luciana Melo Garcia¹, Achintyan Gangadharan², Pinaki Banerjee³, Ye Li³, Andy G X Zeng⁴, Hind Rafei³, Paul Lin³, Bijender Kumar³, Sunil Acharya³, May Daher³, Luis Muniz-Feliciano³, Gary M Deyter³, Gabriel Dominguez³, Jeong Min Park³, Francia Reyes Silva³, Ana Karen Nunez Cortes³, Rafet Basar³, Nadima Uprety³, Mayra Shanley³, Mecit Kaplan³, Enli Liu³, Elizabeth J Shpall³, Katayoun Rezvani⁵

Affiliations

¹ Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Medicine, Université Laval, Quebec City, QC G1V 0A6, Canada; Hematology-Oncology Service, CHU de Québec - Université Laval, Quebec City, QC G1V 0A6, Canada.
² Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Cancer Biology PhD Program, University of South Florida, Tampa, FL 33616, USA.
³ Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Princess Margaret Cancer Center, University Healthy Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁵ Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: [email protected].

PMID: 39754720
DOI: 10.1016/j.celrep.2024.115122

Abstract

CD226 plays a vital role in natural killer (NK) cell cytotoxicity, interacting with its ligands CD112 and CD155 to initiate immune synapse formation, primarily through leukocyte function-associated-1 (LFA-1). Our study examined the role of CD226 in NK cell surveillance of acute myeloid leukemia (AML). NK cells in patients with AML had lower expression of CD226. CRISPR-Cas9 deletion of CD226 led to reduced LFA-1 recruitment, poor synapse formation, and decreased NK cell anti-leukemic activity. Engineering NK cells to express a chimeric antigen receptor targeting the AML antigen CD38 (CAR38) could overcome the need for CD226 to establish strong immune synapses. LFA-1 blockade reduced CAR38 NK cell activity, and this depended on the CD38 expression levels of AML cells. This suggests parallel but potentially cooperative roles for LFA-1 and CAR38 in synapse formation. Our findings suggest that CAR38 NK cells could be an effective therapeutic strategy to overcome CD226-mediated immune evasion in AML.

Keywords: CAR-NK cell; CD226; CP: Cancer; CP: Immunology; LFA-1; acute myeloid leukemia; immune synapse.